RTHα

Resistance to thyroid hormone due to THRA mutation (RTHα): an emerging genetic disease

This page has the ambition to bring all the information currently available to clinicians, in order to facilitate the identification of new cases of this genetic disease (last update Sept 2017). This is important because early detection permits early treatment, preventing adverse neurodevelopmental consequences.

Discovery:

The nuclear receptors of thyroid hormone, TRα1, TRβ1 and TRβ2 are encoded by 2 genes: THRA and THRB (Flamant et al., 2006). While genetic mutations of THRB have been known for a long time in humans, causing a genetic disease now called RTHβ (Refetoff et al., 2014), the discovery of THRA mutations and the associated RTHα disease is more recent (Bochukova et al., 2012). RTHα and RTHβ seem to have similar prevalence, but the diagnostic of RTHα is more difficult. The disease description currently relies on reports of 24 heterozygous patients, corresponding to 13 different mutations of the TRα1 reading frame. RTHα manifests with several features of hypothyroidism without marked reduction in thyroid hormones level (Schoenmakers et al., 2013). It should be stressed that there is at this point no clear distinctive trait or biochemical marker to recognize RTHα. The severity is also quite variable.

Gene and protein structure:

THRA encodes the TRα1 receptor and a number of other proteins. Alternate codon usage produces p43 (Pessemesse et al., 2011) and p28 (Kalyanaraman et al., 2014), two proteins proposed to be involved in non-genomic response to thyroid hormone. Alternate splicing and alternate promoter usage also produce proteins with unknown functions: TRα2, TRα3, TRΔα1 and TRΔα2 (Flamant and Samarut, 2003). Some THRA mutations also alter the production of these proteins. The possible consequences of altering other proteins than TRα1 are unclear.

TRα1 is a 410AA protein divided into a DNA binding domain and a C-terminal ligand binding domain. The C-terminal helix 12 (AA397-407) of the ligand binding domain plays a central role in coactivator recruitment. The 23 mutations found in the 31 identified patients are in the ligand binding domain. Mutations can either alter T3 binding affinity or coactivator recruitment when found in helix 12.

Diagnostic

Most traits are suggestive of congenital hypothyroidism, while T4 and T3 levels remaining within normal range. However the T4/T3 ratio is often low and reverse T3 being subnormal. If compared to carefully matched controls, these biochemical parameters may be the most reliable marker to suspect RTHα. Most patients have short stature, notably short legs. Several adult patients have large head circumference, with increased thickness of the skull. Skeletal malformations are frequent. Mental retardation varies within a broad range. High anxiety in adults has been reported. Chronic constipation, skin tags and anemia have been frequently observed. Three patients have been reported to have epileptic seizures. Seven out of 31 cases were classified as autistic patients.

Treatment:

Most patients are currently treated with excess of levothyroxine to overcome resistance. If patients display residual sensitivity to thyroid hormone, this treatment can provide some benefit, as long as heart rate is not increased. Importantly, excess of thyroid hormone could protect young children from irreversible neurodevelopmental defects.

Type of mutation

DNA

Protein

Position

Country

Carriers in the family

ref

missense

G207E

207

Belgium

1

(van Gucht et al., 2017)

missense

632A>G

D211G

211

NL

1

(van Gucht et al., 2016)

missense

?

A263S

263

Turkey

5

(Demir et al., 2016)

missense

GCG to GTG

A263V

263

UK

3

(Moran et al., 2014)

missense

L274P

274

UK

1

Moran, Unpublished

missense

1044G>T

A348S

348

India

1

(Kalikiri et al., 2017)

missense

1053C>G

H351Q

351

India

1

(Kalikiri et al., 2017)

missense

1075C>G

N359Y

359

France

1

(Espiard et al., 2015)

missense

1099C>A

L367M

367

India

1

(Kalikiri et al., 2017)

frameshift

?

C380fs387X

380

Turkey

1

(Demir et al., 2016)

missense

1144G>C

A382P

382

India

1

(Kalikiri et al., 2017)

frameshift

c1144delG

A382PfsX7

382

UK

1

(Moran et al., 2013)

missense

?

R384H

384

Turkey

2

(Demir et al., 2016)

missense

?

R384C

384

Canada

1

(Yuen et al., 2015)

missense

1176C>A,

C392X

392

Poland

1

(Tylki-Szymanska et al., 2015)

frameshift

1nt insert

F397fs406X

397

Greece

2

(van Mullem et al., 2013)

missense

1193C>G

P398R

398

Poland

1

(Tylki-Szymanska et al., 2015)

missense

1202T>C

F401S

401

India

1

(Kalikiri et al., 2017)

missense

1207G>A

E403K

403

Poland

1

(Tylki-Szymanska et al., 2015)

missense

1207G>A

E403K

403

Poland

2

(Tylki-Szymanska et al., 2015)

missense

1207G>T

E403X

403

UK

1

(Bochukova et al., 2012)

missense

1207G>T

E403X

403

Poland

1

(Tylki-Szymanska et al., 2015)

missense

1213T>C

F405L

405

India

1

(Kalikiri et al., 2017)

Total

25

23

19

31

Mouse models have been generated earlier and extensively analyzed (review in (Flamant and Gauthier, 2013). 4 mutations equivalent to RTHα have been created by homologous recombination: R384C (Tinnikov et al., 2002), P398H (Liu et al., 2003), L400R (Quignodon et al., 2007) and PV in which the C-terminus of TRα1 has been replaced by a peptide found in TRβ1 mutant created by a frameshift (Kaneshige et al., 2001).